Journal of Alzheimer's Disease - Volume 87, issue 2

Authors: Low, Serena | Goh, Kiat Sern | Ng, Tze Pin | Moh, Angela | Ang, Su Fen | Wang, Jiexun | Ang, Keven | Tang, Wern Ee | Lim, Ziliang | Subramaniam, Tavintharan | Sum, Chee Fang | Lim, Su Chi

Article Type: Research Article

Abstract: Background: The association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use and cognitive function in type 2 diabetes remains unclear. Objective: Explore the association between SGLT2i and longitudinal changes in cognitive function in adults with type 2 diabetes (T2DM) and assessed the cognitive domains which were impacted by SGLT2i. Methods: We conducted a prospective cohort study of 476 patients aged 60.6±7.4 years with follow-up period up to 6.4 years. Data on SGLT2i use was derived from questionnaire and verified with clinical database. We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. The association …between SGLT2i use and rate of RBANS score change was examined using multiple linear regression. Results: There were 138 patients (29.0%) on SGLT2i, including 84 (17.7%) for < 3 years and 54 (11.3%) for ≥3 years. SGLT2i use was positively associated with RBANS total score increase in language (coefficient 0.60; 95% CI 0.10–1.11; p  = 0.019) in unadjusted analysis. This positive association persisted in fully adjusted model (coefficient 0.74; 95% CI 0.12 to 1.36; p  = 0.019). SGLT2i use for ≥3 years was positively associated with RBANS score increase globally and in language domain in fully adjusted analysis with coefficients 0.54 (95% CI 0.13 to 0.95; p  = 0.010) and 1.12 (95% CI 0.27 to 1.97; p  = 0.010) respectively. Conclusion: Our findings revealed a previously unobserved association between ≥3 years SGLT2i use and improved cognitive scores globally and in language domain and executive function. Future studies should investigate the role of SGLT2i in ameliorating cognitive decline. Show more

Keywords: Cognitive function, sodium-glucose co-transporter-2 inhibitors, type 2 diabetes

DOI: 10.3233/JAD-215678

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 635-642, 2022

Authors: Lazarou, Ioulietta | Georgiadis, Kostas | Nikolopoulos, Spiros | Oikonomou, Vangelis P. | Stavropoulos, Thanos G. | Tsolaki, Anthoula | Kompatsiaris, Ioannis | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Visual short-term memory (VSTMT) and visual attention (VAT) exhibit decline in the Alzheimer’s disease (AD) continuum; however, network disruption in preclinical stages is scarcely explored. Objective: To advance our knowledge about brain networks in AD and discover connectivity alterations during VSTMT and VAT. Methods: Twelve participants with AD, 23 with mild cognitive impairment (MCI), 17 with subjective cognitive decline (SCD), and 21 healthy controls (HC) were examined using a neuropsychological battery at baseline and follow-up (three years). At baseline, the subjects were examined using high density electroencephalography while performing a VSTMT and VAT. For exploring …network organization, we constructed weighted undirected networks and examined clustering coefficient, strength, and betweenness centrality from occipito-parietal regions. Results: One-way ANOVA and pair-wise t -test comparisons showed statistically significant differences in HC compared to SCD (t (36) = 2.43, p  = 0.026), MCI (t (42) = 2.34, p  = 0.024), and AD group (t (31) = 3.58, p  = 0.001) in Clustering Coefficient. Also with regards to Strength, higher values for HC compared to SCD (t (36) = 2.45, p  = 0.019), MCI (t (42) = 2.41, p  = 0.020), and AD group (t (31) = 3.58, p  = 0.001) were found. Follow-up neuropsychological assessment revealed converge of 65% of the SCD group to MCI. Moreover, SCD who were converted to MCI showed significant lower values in all network metrics compared to the SCD that remained stable. Conclusion: The present findings reveal that SCD exhibits network disorganization during visual encoding and retrieval with intermediate values between MCI and HC. Show more

Keywords: Alzheimer’s disease, brain networks, electroencephalography, mild cognitive impairment, subjective cognitive decline, visual attention, visual short-term memory

DOI: 10.3233/JAD-215421

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 643-664, 2022

Authors: Wang, Xiaoxin | Sun, Hongru | Pan, Sijia | Bai, Xiao | Zhu, Zhuolin | Zhang, Runan | Li, Chunlong | Chen, Yang | Bao, Meitong | Zhang, Kewei | Feng, Rennan

Article Type: Research Article

Abstract: Background: Some observational studies indicated the associations of relative carbohydrate, sugar, fat, and protein intake and Alzheimer’s disease (AD). But it remains unclear whether the associations are causal. Objective: This study aimed to identify the effects of relative carbohydrate, sugar, fat, and protein intake in the diet on AD. Methods: A two-sample Mendelian randomization was employed. Finally, 14 independent lead SNPs remained in the Social Science Genetic Association Consortium. These SNPs of relative carbohydrate, sugar, fat, and protein intake at the level of genome-wide significance (p  < 5×10–8 ) were used as instrumental variables. The summary data …for AD were acquired from the International Genomics of Alzheimer’s Project with a total of 54,162 individuals (17,008 AD patients and 37,154 control participants). Results: This two-sample Mendelian randomization indicated that increased relative protein intake (per 1 standard deviation) causally decreased the AD risk (OR = 0.48, 95% CI: 0.24–0.95, p  = 0.036), and increased relative fat intake may decrease the risk of AD (OR = 0.22, 95% CI: 0.06–0.86, p  = 0.029). No statistical significance with AD risk was seen for relative carbohydrate or relative sugar intake. Conclusion: A higher relative intake of protein can causally reduce the risk of AD in the elderly. Additionally, a higher relative intake of fat may be protective against AD. No evidence showed that AD was associated with relative carbohydrate and sugar intake. Show more

Keywords: Alzheimer’s disease, dietary carbohydrates, dietary fats, dietary proteins, Mendelian randomization analysis

DOI: 10.3233/JAD-215535

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 665-673, 2022

Authors: Wei, Tao | Guo, Zheng | Wang, Zhibin | Li, Cancan | Zhu, Wei | Zheng, Yulu | Yin, Yunsi | Mi, Yingxin | Xia, Xinyi | Hou, Haifeng | Tang, Yi

Article Type: Research Article

Abstract: Background: Extensive studies put forward the association between Alzheimer’s disease (AD) and psychiatric disorders; however, it remains unclear whether these associations are causal. Objective: We aimed to assess the potential causal relationship between major psychiatric disorders and AD. Methods: A bidirectional two-sample Mendelian randomization (MR) was applied to evaluate potential causality between five psychiatric disorders and AD by selecting the single-nucleotide polymorphisms from the genome-wide association studies as instrumental variables. Inverse-variance weighted (IVW) method was used as the main analyzing approach to estimate possible causal effects, alternative methods including MR-Egger, the MR pleiotropy residual sum and …outlier, and leave-one-out analysis method were implemented as sensitivity analyzing approaches to ensure the robustness of results. Results: All forward and reverse MR analyses consistently suggested absent causal relations between psychiatric disorders and AD risk [forward IVW: ORADHD , 1.030, 95% CI, 0.908–1.168, p  = 0.674; ORanxiety disorders , 0.904, 95% CI, 0.722–1.131, p  = 0.377; ORASD , 0.973, 95% CI, 0.746–1.272, p  = 0.846; ORBIP , 1.033, 95% CI, 0.925–1.153, p  = 0.564; and ORschizophrenia , 1.039, 95% CI, 0.986–1.095, p  = 0.156; reverse IVW: ORADHD , 0.993, 95% CI, 0.954–1.034, p  = 0.746; ORanxiety disorders , 1.000, 95% CI, 0.999–1.000, p  = 0.898; ORASD , 1.001, 95% CI, 0.962–1.042, p  = 0.949; ORBIP , 0.997, 95% CI, 0.966–1.028, p  = 0.831; and ORschizophrenia , 1.013, 95% CI, 0.978–1.051, p  = 0.466]. Conclusion: There is no significant evidence supporting the causal association between the five major psychiatric disorders and AD. Show more

Keywords: Alzheimer’s disease, causality, genetic association, Mendelian randomization, psychiatric disorders

DOI: 10.3233/JAD-220010

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 675-684, 2022

Authors: Sivasaravanaparan, Mithula | Olesen, Louise Ørum | Severino, Maurizio | von Linstow, Christian Ulrich | Lambertsen, Kate Lykke | Gramsbergen, Jan Bert | Hasselstrøm, Jørgen | Metaxas, Athanasios | Wiborg, Ove | Finsen, Bente

Article Type: Research Article

Abstract: Background: Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer’s disease, in addition to exerting an anti-depressant action. Objective: To investigate the efficacy of chronic treatment with the SSRI paroxetine, in mitigating Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of 18-month-old APP swe /PS1 ΔE9 mice. Methods: Plaque-bearing APP swe /PS1 ΔE9 and wildtype mice were treated with paroxetine per os at a dose of 5 mg/kg/day, from 9 to 18 months of age. The per os treatment …was monitored by recording of the body weights and serum paroxetine concentrations, and by assessment of the serotonin transporter occupancy by [3 H]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APP swe /PS1 ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ42 /Aβ40 ratio by ELISA. Results: Paroxetine treatment led to > 80% serotonin transporter occupancy. The treatment increased the body weight of wildtype mice, but not of APP swe /PS1 ΔE9 mice. The treatment had no effect on the Aβ plaque load (p  = 0.39), the number and size of plaques, or the Aβ plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the Aβ plaque load or Aβ42 /Aβ40 ratio in APP swe /PS1 ΔE9 mice at 12 months. Conclusion: Our results show that chronic treatment with the SSRI paroxetine does not mitigate Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of APP swe /PS1 ΔE9 mice. Show more

Keywords: Cerebral amyloidosis, chronic paroxetine treatment, hippocampus, microgliosis, neurogenesis, serotonin selective reuptake inhibitors, serotonin transporter occupancy, stereology, Y-maze

DOI: 10.3233/JAD-220019

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 685-699, 2022

Authors: Chung, Seok Jong | Chang, Yoonkyung | Jeon, Jimin | Shin, Jae Il | Song, Tae-Jin | Kim, Jinkwon

Article Type: Research Article

Abstract: Background: Identification of patients at high susceptibility and high risk of developing serious complications related to coronavirus disease 2019 (COVID-19) infection is clinically important in the face of the COVID-19 pandemic. Objective: To investigate whether patients with Alzheimer’s disease (AD) are more susceptible to COVID-19 infection and whether they have a higher risk of developing serious complications. Methods: We retrospectively reviewed the Korean nationwide population-based COVID-19 dataset for participants who underwent real-time reverse transcription polymerase chain reaction assays for COVID-19 between January 1 and June 4, 2020. A 1 : 3 ratio propensity score matching and binary logistic …regression analysis were performed to investigate the association between AD and the susceptibility or severe complications (i.e., mechanical ventilation, intensive care unit admission, or death) of COVID-19. Results: Among 195,643 study participants, 5,725 participants had AD and 7,334 participants were diagnosed with COVID-19. The prevalence of participants testing positive for COVID-19 did not differ according to the presence of AD (p  = 0.234). Meanwhile, AD was associated with an increased risk of severe COVID-19 complications (OR 2.25 [95% CI 1.54–3.28]). Secondary outcome analyses showed that AD patients had an increased risk for mortality (OR 3.09 [95% CI 2.00–4.78]) but were less likely to receive mechanical ventilation (OR 0.42 [95% CI 0.20–0.87]). Conclusion: AD was not associated with increased susceptibility to COVID-19 infection, but was associated with severe COVID-19 complications, especially with mortality. Early diagnosis and active intervention are necessary for patients with AD suspected COVID-19 infection. Show more

Keywords: Alzheimer disease, COVID-19, mortality, prognosis, susceptibility

DOI: 10.3233/JAD-220031

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 701-710, 2022

Authors: Jian, Jie-Ming | Fan, Dong-Yu | Cheng, Yuan | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Chen, Yang | Zhang, Yuan | Zeng, Gui-Hua | Tan, Cheng-Rong | Liu, Yu-Hui | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: The G protein-coupled receptor P2RY2 protein of the purinergic receptor family is involved in the pathogenesis of Alzheimer’s disease (AD). Naturally occurring antibodies against P2RY2 (NAbs-P2RY2) are present in human plasma, with their clinical relevance in AD unknown. Objective: To explore the alteration of NAbs-P2RY2 in AD patients and its associations with biomarkers and cognition of AD patients. Methods: The levels of naturally occurring antibodies against the four extracellular domains of P2RY2 (NAbs-P2RY2-1, NAbs-P2RY2-2, NAbs-P2RY2-3, and NAbs-P2RY2-4) were measured in the plasma of 55 AD patients, 28 non-AD dementia patients, and 70 cognitively normal participants. …The correlations of autoantibody levels with cognitive scale scores, AD plasma biomarkers, and brain amyloid burden were examined. Results: NAbs-P2RY2-1, NAbs-P2RY2-3, and NAbs-P2RY2-4 were reduced in AD patients. Plasma levels of NAbs-P2RY2-2 and NAbs-P2RY2-3 levels were positively associated with cognitive and functional performances. Among these antibodies, plasma NAbs-P2RY2-2 levels were positively associated with plasma amyloid-β 42 levels. While plasma NAbs-P2RY2-3 levels were negatively associated with brain amyloid burden in AD patients. Conclusion: These findings indicate an alteration of humoral immunity against P2RY2 in AD patients. Further mechanistical investigations are needed to reveal the role of NAbs-P2RY2 in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, G protein-coupled receptor, naturally occurring antibodies, P2RY2

DOI: 10.3233/JAD-215611

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 711-719, 2022

Authors: Zhang, Peng-Fei | Wang, Zuo-Teng | Liu, Ying | Hu, Hao | Sun, Yan | Hu, He-Ying | Ma, Ya-Hui | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Inflammation plays a role in occurrence and progression of Alzheimer’s disease (AD). Whether peripheral immune cells are involved in major pathological processes including amyloid-β plaques and tau tangles is still controversial. Objective: We aimed to examine whether peripheral immune cells counts were associated with early changes in cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively intact older adults. Methods: This study included 738 objective cognitive normal participants from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) database. Group comparisons of peripheral immune cells counts were tested by analysis of covariance. Multiple linear regression models were …used to examine the associations of peripheral immune cells counts with CSF AD biomarkers. Results: In preclinical AD, peripheral lymphocytes and eosinophils changed dynamically along with disease progression. Consistently, regression analysis showed that lymphocytes and eosinophils were associated with Aβ pathology. There were no interaction effects of peripheral immune cells counts with APOE ɛ4, gender, age, and educate. Eosinophil to lymphocyte ratio were also significantly associated with Aβ-related biomarkers. Conclusion: Our findings showed the relationship between peripheral immune cells and Aβ pathological biomarkers, which indicated that peripheral immune might play a role in progression of AD pathology. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, inflammation, pathology, peripheral immune cells

DOI: 10.3233/JAD-220057

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 721-730, 2022

Authors: Sommerlad, Andrew | Park, Hee Kyung | Marston, Louise | Livingston, Gill

Article Type: Research Article

Abstract: Background: Apathy in dementia is common and associated with worse disease outcomes. Objective: To describe the longitudinal course of apathy in dementia and identify associated sociodemographic and disease-related factors. Methods: Prospective cohort study of UK care home residents with dementia. At baseline, 4, 8, 12, and 16 months, care home staff rated apathy using the Neuropsychiatric Inventory (clinically-significant apathy if≥4), dementia severity, and provided other sociodemographic information about each participant. We examined the prevalence and persistence of apathy and, in mixed linear models, its association with time, age, sex, dementia severity, antipsychotic use, and baseline apathy …and other neuropsychiatric symptoms. Results: Of 1,419 included participants (mean age 85 years (SD 8.5)), 30% had mild dementia, 33% moderate, and 37% severe. The point prevalence of clinically-significant apathy was 21.4% (n  = 304) and the 16-month period prevalence was 47.3% (n  = 671). Of participants with follow-up data, 45 (3.8%) were always clinically-significantly apathetic, 3 (0.3%) were always sub-clinically apathetic, and 420 (36.2%) were never apathetic until death or end of follow-up. In adjusted models, apathy increased over time and was associated with having more severe dementia, worse baseline apathy and other neuropsychiatric symptoms. Conclusion: It is important for clinicians to know that most people with dementia are not apathetic, though it is common. Most of those with significant symptoms of apathy improve without specific treatments, although some also relapse, meaning that intervention may not be needed. Future research should seek to target those people with persistent severe apathy and test treatments in this group. Show more

Keywords: Apathy, care homes, cohort study, dementia, neuropsychiatric inventory, neuropsychiatric symptoms

DOI: 10.3233/JAD-215623

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 731-740, 2022

Authors: Martínez-Herrera, Melchor | Figueroa-Gerstenmaier, Susana | López-Camacho, Perla Y. | Millan-Pacheco, Cesar | Balderas-Altamirano, Miguel A. | Mendoza-Franco, Graciela | García-Sierra, Franciscos | Zavala-Ocampo, Lizeth M. | Basurto-Islas, Gustavo

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) fibrils induce cognitive impairment and neuronal loss, leading to onset of Alzheimer’s disease (AD). The inhibition of Aβ aggregation has been proposed as a therapeutic strategy for AD. Pristine C60 has shown the capacity to interact with the Aβ peptide and interfere with fibril formation but induces significant toxic effects in vitro and in vivo . Objective: To evaluate the potential of a series of C60 multiadducts to inhibit the Aβ fibrillization. Methods: A series of C60 multiadducts with four to six diethyl malonyl and their corresponding disodium-malonyl substituents …were synthesized as individual isomers. Their potential on Aβ fibrillization inhibition was evaluated in vitro , in cellulo , and silico . Antioxidant activity, acetylcholinesterase inhibition capacity, and toxicity were assessed in vitro . Results: The multiadducts modulate Aβ fibrils formation without inducing cell toxicity, and that the number and polarity of the substituents play a significant role in the adducts efficacy to modulate Aβ aggregation. The molecular mechanism of fullerene-Aβ interaction and modulation was identified. Furthermore, the fullerene derivatives exhibited antioxidant capacity and reduction of acetylcholinesterase activity. Conclusion: Multiadducts of C60 are novel multi-target-directed ligand molecules that could hold considerable promise as the starting point for the development of AD therapies. Show more

Keywords: Alzheimer’s disease, fullerenes, molecular dynamics, nanoparticles, polymerization, therapy

DOI: 10.3233/JAD-215412

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 741-759, 2022